X-ray crystal structure and specificity of the <i>Toxoplasma gondii</i> ME49 <i>Tg</i>APN2

Marijanovic, Emilia M.; Świderska, K.; Andersen, James S.; Aschenbrenner, Jasmin C; Webb, Chaille T; Drąg, Marcin; Drinkwater, N.; McGowan, Sheena

doi:10.1042/bcj20200569

Cited by 2 publications

(7 citation statements)

References 51 publications

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“…The crystallographic structure of T. gondii ME49 TgAPN2 was retrieved from the Protein Data Bank using PDB ID 6OIU [ 2 , 52 ]. The PDB structure was selected due to its recent submission to the database and good resolution quality compared to other available structures.…”

Section: Methodsmentioning

confidence: 99%

“…The M1 aminopeptidases (also termed aminopeptidase N) are found in living systems and are anchored in cell membrane [ 1 ]. These enzymes are vital from a functionality perspective and are important in cell growth, development, maintenance, and defense [ 2 ]. They are documented as potential candidates for novel drugs and regarded as potential immunoprotected targets [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

“…Targeted inhibition of PfA-M1 has been unveiled to stop P. falciparum inhibition in both laboratory and animal murine models [ 5 ]. Toxoplasma gondii is a causative agent of toxoplasmosis, which can cause serious complications in pregnant women [ 2 , 6 , 7 , 8 , 9 ]. The congenital pathogen infection results in mental retardation, miscarriage, and hearing and vision problems [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

“…The M1 aminopeptidases are of three types in the T. gondii ME49 strain—TgAPN1, TgAPN2, and TgAPN3—and encoded by genes present on different chromosomes [ 2 ]. TgAPN1 is experimentally active and shown as immunogenic.…”

Section: Introductionmentioning

confidence: 99%

“…The biological function of TgAPN2 is still not clear; however, it is predicted to play a role in tachyzoite growth. Its upregulation in bradyzoites also makes it an important target for drug development [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

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Targeting Toxoplasma gondii ME49 TgAPN2: A Bioinformatics Approach for Antiparasitic Drug Discovery

Altharawi

2023

Molecules

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As fewer therapeutic options are available for treating toxoplasmosis, newer antiparasitic drugs that can block TgAPN2 M1 aminopeptidase are of significant value. Herein, we employed several computer-aided drug-design approaches with the objective of identifying drug molecules from the Asinex library with stable conformation and binding energy scores. By a structure-based virtual screening process, three molecules—LAS_52160953, LAS_51177972, and LAS_52506311—were identified as promising candidates, with binding affinity scores of −8.6 kcal/mol, −8.5 kcal/mol, and −8.3 kcal/mol, respectively. The compounds produced balanced interacting networks of hydrophilic and hydrophobic interactions, vital for holding the compounds at the docked cavity and stable binding conformation. The docked compound complexes with TgAPN2 were further subjected to molecular dynamic simulations that revealed mean RMSD for the LAS_52160953 complex of 1.45 Å), LAS_51177972 complex 1.02 Å, and LAS_52506311 complex 1.087 Å. Another round of binding free energy validation by MM-GBSA/MM-PBSA was done to confirm docking and simulation findings. The analysis predicted average MM-GBSA value of <−36 kcal/mol and <−35 kcal/mol by MM-PBSA. The compounds were further classified as appropriate candidates to be used as drug-like molecules and showed favorable pharmacokinetics. The shortlisted compounds showed promising biological potency against the TgAPN2 enzyme and may be used in experimental validation. They may also serve as parent structures to design novel derivatives with enhanced biological potency.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Targeting Toxoplasma gondii ME49 TgAPN2: A Bioinformatics Approach for Antiparasitic Drug Discovery

Altharawi

2023

Molecules

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Metallopeptidases as Key Virulence Attributes of Clinically Relevant Protozoa: New Discoveries, Perspectives, and Frontiers of Knowledge

Rigo

Cardoso

Galego

et al. 2023

CPPS

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This article provides a comprehensive review of several subclasses of metallo-type peptidases expressed by the main clinically relevant protozoa, including Plasmodium spp., Toxoplasma gondii, Cryptosporidium spp., Leishmania spp., Trypanosoma spp., Entamoeba histolytica, Giardia duodenalis, and Trichomonas vaginalis. These species comprise a diverse group of unicellular eukaryotic microorganisms responsible for widespread and severe human infections. Metallopeptidases, defined as hydrolases with activity mediated by divalent metal cation, play important roles in the induction and maintenance of parasitic infections. In this context, metallopeptidases can be considered veritable virulence factors in protozoa with direct/indirect participation in several key pathophysiological processes, including adherence, invasion, evasion, excystation, central metabolism, nutrition, growth, proliferation, and differentiation. Indeed, metallopeptidases have become an important and valid target to search for new compounds with chemotherapeutic purposes. The present review aims to gather updates regarding metallopeptidase subclasses, exploring their participation in protozoa virulence as well as investigating the similarity of peptidase sequences through bioinformatics techniques in order to discover clusters of greater relevance for the development of new broad antiparasitic molecules.

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X-ray crystal structure and specificity of the Toxoplasma gondii ME49 TgAPN2

Cited by 2 publications

References 51 publications

Targeting Toxoplasma gondii ME49 TgAPN2: A Bioinformatics Approach for Antiparasitic Drug Discovery

Targeting Toxoplasma gondii ME49 TgAPN2: A Bioinformatics Approach for Antiparasitic Drug Discovery

Metallopeptidases as Key Virulence Attributes of Clinically Relevant Protozoa: New Discoveries, Perspectives, and Frontiers of Knowledge

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